Clinical Research and Development in the Pharmaceutical and Biotechnology Industry

Robert Anderson, MHA, CCRA, CCRCP Director, Clinical Trials Administration The CRA Training Institute, Houston

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Objectives
To understand the drug development process To understand the phases and components of the clinical research process To appreciate the history behind the regulations in the clinical development process To understand the current regulations involved with the clinical research process
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Healthcare Industry Players

Physician Insurance Company

Patient Care

Hospital

Pharmaceutical Industry

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Drug Discovery Process

Target Selection Target Validation & lead optimization

Proof of Concept Clinical Trials

Pre-clinical Phase

Compound Selection (5,000 10,000)

2 4 Years

Proof of Concept Outcome (250)

Clinical Phases I, II III, IIIB*

*Key variable guiding development time

Drug Registration FDA Approval Marketing Introduction

Marketing (Phase IV Clinical Trials)

(5)

4 7 Years

(1)

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Clinical Trials: What Are They?

An organized research study designed to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease (such as cancer).

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The Players in Clinical Research

Investigator Site

Sponsor

Patient

CRO

IRB

SMO

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Clinical Trials Process and Associated Regulatory Process

Phase II End of Phase II Meeting

Pre-IND Meeting IND Application

Phase I

Phase II

Phase III Pre-NDA Meeting

Phase IV

File NDA

Drug Approval

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Phases of Clinical Trials

Category Phase I # of Participants Less than 10 Purpose Tests how to administer a new therapy, exam, or preventive option Test patients responses to a new therapy, exam, or preventive option Compares new therapy exam or preventive option to a standard one For marketing purposes, to compare the effectiveness of two therapies already on the market or to study new uses of therapies

Phase II

30-40

Phase III

100-1000+

Phase IV

Varies

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Tasks Involved to Develop/Support Clinical Trials

Protocol development Volunteer recruitment Clinical conduct (management) Monitoring Data management Clinical statistics Medical writing Quality assurance

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What is Involved in a Clinical Trial?

File IND application
Develop protocol Submit to FDA for comment or no action Sites enroll patients Patients cycle through study Capture: Adverse events, vital signs, study drug adherence, QOL questionnaires captured on Case Report Forms

Select investigational sites based on # of patients needed for the study

Regulatory requirements for each trial at each site 1571 or 1572 PIs CV Financial disclosure forms Informed consent IRB approval

Patients exit study Data collected and cleaned Sites closed Write study report Add study to NDA

Initiate site(s)
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Clinical Trials Benefits & Risks

Possible Benefits of Trials Having access to potentially more effective therapies than those currently available Receiving quality medical care from leading physicians Being closely monitored for possible negative effects Sometimes receiving treatment at a reduced rate or free of charge Helping to further new research that may result in significant medical advances For patients in cancer therapy trials assigned to control groups, they still receive the top standard therapy available today Possible Risks of Trials Patients may not receive the therapy under investigation (may receive a placebo inactive pill instead) The new therapy may not be more effective than the standard, thoroughly tested therapy In Phase I trails, not knowing the safety consequences of the new therapy (risk is less in Phase III trials) New therapy may have unexpected, possibly severe side effects or may be less effective than standard of care Insurance companies may not cover all costs of clinical trials

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Clinical Trial Standard Language

Protocol The planned course of action for the clinical trial. The protocol is established prior to the start of the trial and states the number of participants, eligibility requirements, agents that will be used, dosages, duration, how data is collected, etc.

Investigator
Sponsor

A researcher in a clinical trial.

The part of parties responsible for funding the clinical trial.

Institutional Review Board (IRB)

Informed Consent

An independent board of scientists, physicians, and nurses who review the clinical trial protocol to ensure patient safety.
A patients decision to participate in the clinical trial after being informed of the potential benefits and risks of participation. Participants may withdraw their consent at any time and leave the trial.

Double blind

Term used to describe a clinical trial in which neither the patient nor the researcher knows which agents are being administered to which patients. This helps prevent bias.
The group of participants receiving the new preventive or treatment agent that is being evaluated in the clinical trial.

Invention group
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Clinical Trial Standard Language, continued

Control group The group of participants receiving a standard treatment or placebo (see below) that is being compared to the new agent in the clinical trial. Assigning participants by chance to either the intervention group or the control group. Randomization is often done with a computer. An inactive substance that may be given to participant sin a clinical trial. Sometimes called a sugar pill.

Randomization Placebo

Follow-up
Prospective study Retrospective study

Monitoring of participants for a specified time after the clinical trial is completed.
A study of a group of patients that is conducted as they are undergoing a treatment or preventive measure. A study of a group of patients after they have already undergone a treatment or preventive measure. Recall bias, unintentional inaccurate reporting of certain information, can sometimes influence a retrospective study.

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History Behind Regulations of Clinical Trials

Regulations often result in response to abuse of human research subjects and concerns about the validity of data and conclusions from clinical trials. The primary vehicles for human subject protection are IRBs and informed consent. The Declaration of Helsinki and the Belmont Report are critical documents for the protection of human subjects in research. The FDA, by means of PDUFA and FDAMA, has made significant gains in speeding the process of making new drugs available for patients who need them. Current problems with clinical trials and trial oversight may well lead to increased regulation.
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Regulations for Clinical Trials

The FDA regulations pertaining to clinical trials are found in 21 CFR Parts 11, 50, 54, 56, 312 and 314. The ICH Guidelines for Good Clinical Practice should be followed in clinical trials. The FDA publishes many guidelines and information sheets pertaining to the appropriate conduct of clinical trials. Good clinical practices are the ethical and clinical standard for designing, conducting, analyzing, monitoring and reporting on clinical trials.
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Health Outcomes

Health outcomes studies examine the clinical, economic and quality-oflife outcomes of pharmacotherapy. Health outcomes research expands upon the FDA-mandated efficacy and safety endpoints to give a fuller picture of the outcomes experienced by a patient. It is a relatively new discipline that combines a number of fields of study, including medicine, epidemiology, statistics, economics and psychometrics. Early in development, companies may be interested in documenting the epidemiology and cost burden of a particular disease state. As a compound moves through to Phase II and II, behavioral, humanistic and economic endpoints may be incorporated into registration trials. Concurrently, economic models may be created to quantify the economic benefit of the new therapy. Once a compound is launched, a variety of research services may be utilized, including registries, Phase IIIb/IV comparative studies and claims analyses.

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Other Issues in the Clinical Research Process

National Institutes of Health Special populations Data Safety Monitoring Boards Orphan drugs

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